Treatment of intrahepatic cholestatic diseases

ABSTRACT

Treatment of intrahepatic cholestatic diseases by therapy with seladelpar or a salt thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.17/024,971, filed 18 Sep. 2020 and now allowed; which is a continuationof U.S. application Ser. No. 16/597,313, filed 9 Sep. 2019 and now U.S.patent Ser. No. 10/813,895; which is a continuation of U.S. applicationSer. No. 16/367,660, filed 28 Mar. 2019 and now U.S. patent Ser. No.10/478,411; which is a continuation of U.S. application Ser. No.15/496,875, filed 25 Apr. 2017 and now U.S. patent Ser. No. 10/272,058.U.S. application Ser. No. 15/496,875 claims the priority under 35 USC119(e) of U.S. Application No. 62/343,688, filed 31 May 2016, entitled“Treatment of intrahepatic cholestatic diseases”, which is incorporatedinto this application by reference. U.S. application Ser. No. 15/496,875is also a continuation-in-part of U.S. application Ser. No. 15/271,460,filed 21 Sep. 2016 and now U.S. Pat. No. 9,808,436; which is acontinuation of U.S. application Ser. No. 14/663,027, filed 19 Mar. 2015and now U.S. Pat. No. 9,486,428; and U.S. application Ser. No.14/663,027 claims the priority under 35 USC 119(e) of U.S. ApplicationNo. 61/968,037, filed 20 Mar. 2014; each of these applications beingentitled “Treatment of intrahepatic cholestatic diseases”.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to the treatment of intrahepatic cholestaticdiseases.

Description of the Related Art

Intrahepatic Cholestatic Diseases

Cholestasis is a condition in which the flow of bile from the liver tothe duodenum is slowed or blocked. Cholestasis may be dividedconveniently into two types: intrahepatic cholestasis, inside the liver,where bile formation is disturbed by conditions such as variousdiseases, extended intravenous nutrition, or as a side effect of certaindrugs (such as some antibiotics); and extrahepatic cholestasis,occurring outside the liver, typically where the flow of bile isobstructed by a mechanical partial or complete closure of the bile duct,such as by bile duct tumors, cysts, bile duct stones, strictures, orpressure on the bile duct; though primary sclerosing cholangitis (PSC)may be intrahepatic or extrahepatic. Common symptoms of cholestasisinclude fatigue, pruritus (itching), jaundice, and xanthoma (deposits ofcholesterol-rich material under the skin). The effects of cholestasisare profound and widespread, leading to worsening liver disease withsystemic illness, liver failure, and the need for liver transplantation.

Intrahepatic cholestatic diseases include, in order of decreasingfrequency, primary biliary cholangitis (PBC, formerly known as primarybiliary cirrhosis), primary sclerosing cholangitis (PSC), progressivefamilial intrahepatic cholestasis (PFIC), and Alagille syndrome (AS),

PBC is an autoimmune disease of the liver marked by the slow progressivedestruction of the small bile ducts of the liver, with the intralobularducts affected early in the disease. When these ducts are damaged, bilebuilds up in the liver (cholestasis) and over time damages the tissue,which can lead to scarring, fibrosis and cirrhosis. Recent studies haveshown that it may affect up to 1 in 3,000-4,000 people, with a sex ratioat least 9:1 female to male. There is no cure for PBC, and livertransplantation often becomes necessary; but medication such asursodeoxycholic acid (UDCA, ursodiol) to reduce cholestasis and improveliver function, cholestyramine to absorb bile acids, modafinil forfatigue, and fat-soluble vitamins (vitamins A, D, E, and K, sincereduced bile flow makes it difficult for these vitamins to be absorbed)may slow the progression to allow a normal lifespan and quality of life.UDCA is the only drug approved in the United States to treat PBC.Japanese researchers have reported that the addition of bezafibrate, aperoxisome proliferator-activated receptor-α (PPARa) and pregnane Xreceptor agonist, to UDCA is helpful in treating patients who arerefractory to UDCA monotherapy, improving serum biliary enzymes,cholesterol (C), and triglycerides (TGs).

PSC is a chronic cholestatic liver disease characterized by intra- orextrahepatic biliary duct inflammation and fibrosis, eventually leadingto cirrhosis. The underlying cause of the inflammation is believed to beautoimmunity; and about three-fourths of patients with PSC haveinflammatory bowel disease, usually ulcerative cholitis, though this isreported to vary by country, as is the prevalence (generally reported atabout 1 in 10,000) and sex ratio (generally reported as predominatelymale). Standard treatment includes UDCA, which has been shown to lowerelevated liver enzyme numbers in people with PSC, but has not improvedliver survival or overall survival; and also includes antipruritics,cholestyramine, fat-soluble vitamins, and antibiotics to treatinfections (bacterial cholangitis). In a study reported in 2009,long-term high-dose UDCA therapy was associated with improvement inserum liver tests in PSC but did not improve survival and was associatedwith higher rates of serious adverse events. Liver transplantation isthe only proven long-term treatment.

PFIC refers to a group of three types of autosomal recessive disordersof childhood associated with intrahepatic cholestasis: deficiency offamilial intrahepatic cholestasis 1 (PFIC-1), deficiency of bile saltexport pump (PFIC-2), and deficiency of multidrug resistance protein 3(PFIC-3). They have a combined incidence of 1 in 50,000-100,000. Theonset of the disease is usually before age 2, with PFIC-3 usuallyappearing earliest, but patients have been diagnosed with PFIC even intoadolescence. Patients usually show cholestasis, jaundice, and failure tothrive; and intense pruritus is characteristic. Fat malabsorption andfat soluble vitamin deficiency may appear. Biochemical markers include anormal γ-glutamyl transpeptidase (GGT) in PFIC-1 and PFIC-2, but amarkedly elevated GGT in PFIC-3; while serum bile acid levels aregreatly elevated; though serum cholesterol levels are typically notelevated, as is seen usually in cholestasis, because the disease is dueto a transporter as opposed to an anatomical problem with biliary cells.The disease is typically progressive without liver transplantation,leading to liver failure and death in childhood; and hepatocellularcarcinoma may develop in PFIC-2 at a very early age. Medication withUDCA is common; supplemented by fat-soluble vitamins, cholestyramine,and pancreatic enzymes in PFIC-1.

AS, also known as Alagille-Watson syndrome, syndromic bile duct paucity,and arteriohepatic dysplasia, is an autosomal dominant disorderassociated with liver, heart, eye and skeletal abnormalities, as well ascharacteristic facial features; with an incidence of about 1 in 100,000.The liver abnormalities are narrowed and malformed bile ducts within theliver; and these result in obstruction of bile flow, causing cirrhosis(scarring) of the liver. AS is predominately caused by changes in theJagged1 gene, located on chromosome 20. In 3-5% of cases, the entiregene is deleted (missing) from one copy of chromosome 20; in theremainder, there are changes or mutations in the Jagged1 DNA sequence.In a very small number of cases, less than 1 percent, changes in anothergene, Notch2, result in AS. In about one-third of the cases, themutation is inherited; in about two-thirds, the mutation is new in thatcase. There is no cure for AS, though the severity of liver diseasetypically peaks by 3 to 5 years of age and often resolves by 7 to 8years of age. In some people, the hepatic disease will progress toend-stage liver disease and may require liver transplantation;approximately 15% of patients with AS require liver transplantation. Anumber of different medications, for example UDCA, have been used toimprove bile flow and reduce itching, and many patients are given highdoses of fat-soluble vitamins.

Alkaline phosphatase (ALP) and GGT are key markers of cholestasis. Whilean elevation of one of them alone does not indicate cholestasis, andother parameters would be needed for confirmation, elevation in both ALPand GGT is indicative of cholestasis; and a decrease in both indicatesimprovement of cholestasis. Thus ALP and GGT levels serve as biochemicalmarkers for the presence of biliary pathophysiology present inintrahepatic cholestatic diseases, and ALP level has been used as aprimary outcome marker in clinical studies of intrahepatic diseases suchas PBC (including in the studies leading to FDA approval of obeticholicacid).

Treatments for Intrahepatic Cholestatic Diseases

As mentioned above, UDCA is a common treatment for intrahepaticcholestatic diseases, because of its action in reducing cholestasis andimproving liver function. However, a Cochrane Review of UDCA in PBC in2012 found that, although UDCA showed a reduction in biomarkers of liverpathology, jaundice, and ascites, there was no evidence in the medicalliterature for any benefit of UDCA on mortality or livertransplantation, while its use was associated with weight gain andcosts.

Obeticholic acid (6α-ethylchenodeoxycholic acid, InterceptPharmaceuticals's OCALIVA), a semi-synthetic bile acid analog that is ahighly potent farnesoid X receptor agonist, has recently been approvedby the US FDA for the treatment of PBC. However, the only long-termtreatment for many patients with intrahepatic cholestatic diseases isliver transplantation.

It would be desirable to develop pharmacological treatments forintrahepatic cholestatic diseases.

Seladelpar

Seladelpar (recommended INN) is the compound of the formula

Seladelpar has the chemical name(R)-2-(4-((2-ethoxy-3-(4-(trifluoromethyl)phenoxy)propyl)thio)-2-methylphenoxy)aceticacid [IUPAC name as generated by CHEMDRAW ULTRA 12.0], and the codenumber MBX-8025. Seladelpar and its synthesis, formulation, and use isdisclosed in, for example, U.S. Pat. No. 7,301,050 (compound 15 in Table1, Example M, claim 49), U.S. Pat. No. 7,635,718 (compound 15 in Table1, Example M), and U.S. Pat. No. 8,106,095 (compound 15 in Table 1,Example M, claim 14). Lysine (L-lysine) salts of seladelpar and relatedcompounds are disclosed in U.S. Pat. No. 7,709,682 (seladelpar L-lysinesalt throughout the Examples, crystalline forms claimed).

Seladelpar is an orally active, potent (2 nM) agonist of peroxisomeproliferator-activated receptor-δ (PPARδ). It is specific (>600-foldand >2500-fold compared with PPARa and peroxisome proliferator-activatedreceptor-γ receptors). PPARδ activation stimulates fatty acid oxidationand utilization, improves plasma lipid and lipoprotein metabolism,glucose utilization, and mitochondrial respiration, and preserves stemcell homeostasis. According to U.S. Pat. No. 7,301,050, PPARδ agonists,such as seladelpar, are suggested to treat PPARδ-mediated conditions,including “diabetes, cardiovascular diseases, Metabolic X syndrome,hypercholesterolemia, hypo-high density lipoprotein(HDL)-cholesterolemia, hyper-low density protein (LDL)-cholesterolemia,dyslipidemia, atherosclerosis, and obesity”, with dyslipidemia said toinclude hypertriglyceridemia and mixed hyperlipidemia.

A Phase 2 study of seladelpar L-lysine dihydrate salt in mixeddyslipidemia (6 groups, 30 subjects/group: once daily oral placebo,atorvastatin (ATV) 20 mg, or seladelpar L-lysine dihydrate salt at 50 or100 mg (calculated as the free acid) capsules alone or combined with ATV20 mg, for 8 weeks) has been reported by Bays et al., “MBX-8025, A NovelPeroxisome Proliferator Receptor-δ Agonist: Lipid and Other MetabolicEffects in Dyslipidemic Overweight Patients Treated with and withoutAtorvastatin”, J. Clin. Endocrin. Metab., 96(9), 2889-2897 (2011) andChoi et al., “Effects of the PPAR-δ agonist MBX-8025 on atherogenicdyslipidemia”, Atherosclerosis, 220, 470-476 (2012). Compared toplacebo, seladelpar alone and in combination with ATV significantly(P<0.05) reduced apolipoprotein B-100 by 20-38%, LDL by 18-43%,triglycerides (TGs) by 26-30%, non-HDL-C by 18-41%, free fatty acids by16-28%, and high-sensitivity C-reactive protein by 43-72%; it raisedHDL-C by 1-12% and also reduced the number of patients with themetabolic syndrome and a preponderance of small LDL particles.Seladelpar reduced small/very small LDL particles by 40-48% comparedwith a 25% decrease with ATV; and seladelpar increased large LDLparticles by 34-44% compared with a 30% decrease with ATV. Seladelparsignificantly reduced ALP by 32-43%, compared to reductions of only 4%in the control group and 6% in the ATV group; and significantly reducedGGT by 24-28%, compared to a reduction of only 3% in the control groupand an increase of 2% in the ATV group. Thus seladelpar corrects allthree lipid abnormalities in mixed dyslipidemia—lowers TGs and LDL andraises HDL, selectively depletes small dense LDL particles (92%),reduces cardiovascular inflammation, and improves other metabolicparameters including reducing serum aminotransferases, increases insulinsensitivity (lowers homeostatic model assessment-insulin resistance,fasting plasma glucose, and insulin), lowers GGT and ALP, significantly(>2-fold) reduces the percentage of subjects meeting the criteria formetabolic syndrome, and trends towards a decrease in waist circumferenceand increase in lean body mass. Seladelpar was safe and generallywell-tolerated, and also reduced liver enzyme levels. As explained in USPatent Application Publication No. 2010-0152295, seladelpar converts LDLparticle size pattern I (a predominant LDL particle size of from 25.75nm to 26.34 nm) to pattern A (a predominant LDL particle size of greaterthan 26.34 nm); and from pattern B (a predominant LDL particle size ofless than 25.75 nm) to pattern I or A, where the LDL particle size ismeasured by gradient-gel electrophoresis.

The disclosures of the documents referred to in this application areincorporated into this application by reference.

SUMMARY OF THE INVENTION

This invention is a method of treatment of an intrahepatic cholestaticdisease, comprising administration of seladelpar or a salt thereof.

Because seladelpar lowers alkaline phosphatase and γ-glutamyltranspeptidase, which are elevated in intrahepatic cholestatic diseases,its use will result in a reduction in cholestasis and provide aneffective treatment for these diseases (other drugs, such as thefibrates, which also lower ALP and GGT in dyslipidemic patients, areknown to reduce cholestasis in intrahepatic cholestatic diseases).

Preferred embodiments of this invention are characterized by thespecification and by the features of claims 1 to 11 of this applicationas filed.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Intrahepatic cholestatic diseases” and their treatment are described inthe subsections entitled “Intrahepatic cholestatic diseases” and“Treatments for intrahepatic cholestatic diseases” of the Background ofthe invention.

“Treating” or “treatment” of an intrahepatic cholestatic disease in ahuman includes one or more of:

(1) preventing or reducing the risk of developing an intrahepaticcholestatic disease, i.e., causing the clinical symptoms of anintrahepatic cholestatic disease not to develop in a subject who may bepredisposed to an intrahepatic cholestatic disease but who does not yetexperience or display symptoms of the intrahepatic cholestatic disease(i.e. prophylaxis);(2) inhibiting an intrahepatic cholestatic disease, i.e., arresting orreducing the development of the intrahepatic cholestatic disease or itsclinical symptoms; and(3) relieving an intrahepatic cholestatic disease, i.e., causingregression, reversal, or amelioration of the intrahepatic cholestaticdisease or reducing the number, frequency, duration or severity of itsclinical symptoms.

A “therapeutically effective amount” of seladelpar or an seladelpar saltmeans that amount which, when administered to a human for treating anintrahepatic cholestatic disease, is sufficient to effect treatment forthe intrahepatic cholestatic disease. The therapeutically effectiveamount for a particular subject varies depending upon the age, healthand physical condition of the subject to be treated, the intrahepaticcholestatic disease and its extent, the assessment of the medicalsituation, and other relevant factors. It is expected that thetherapeutically effective amount will fall in a relatively broad rangethat can be determined through routine trial.

“Seladelpar” is described in the subsection entitled “Seladelpar” of theBackground of the invention.

Salts (for example, pharmaceutically acceptable salts) of seladelpar areincluded in this invention and are useful in the methods described inthis application. These salts are preferably formed withpharmaceutically acceptable acids. See, for example, “Handbook ofPharmaceutically Acceptable Salts”, Stahl and Wermuth, eds., VerlagHelvetica Chimica Acta, Zurich, Switzerland, for an extensive discussionof pharmaceutical salts, their selection, preparation, and use. Unlessthe context requires otherwise, reference to seladelpar is a referenceboth to the compound and to its salts.

Because seladelpar contains a carboxyl group, it may form salts when theacidic proton present reacts with inorganic or organic bases. Typicallythe seladelpar is treated with an excess of an alkaline reagent, such ashydroxide, carbonate or alkoxide, containing an appropriate cation.Cations such as Na⁺, K⁺, Ca²⁺, Mg²⁺, and NH₄ ⁺ are examples of cationspresent in pharmaceutically acceptable salts. Suitable inorganic bases,therefore, include calcium hydroxide, potassium hydroxide, sodiumcarbonate and sodium hydroxide. Salts may also be prepared using organicbases, such as salts of primary, secondary and tertiary amines,substituted amines including naturally-occurring substituted amines, andcyclic amines, including isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, and the like. As noted in the “Seladelpar”subsection, seladelpar is currently formulated as its L-lysine dihydratesalt; and seladelpar has also been studied in clinical trials as itscalcium salt.

“Comprising” or “containing” and their grammatical variants are words ofinclusion and not of limitation and mean to specify the presence ofstated components, groups, steps, and the like but not to exclude thepresence or addition of other components, groups, steps, and the like.Thus “comprising” does not mean “consisting of”, “consistingsubstantially of”, or “consisting only of”; and, for example, aformulation “comprising” a compound must contain that compound but alsomay contain other active ingredients and/or excipients.

Formulation and Administration

The seladelpar may be administered by any route suitable to the subjectbeing treated and the nature of the subject's condition. Routes ofadministration include administration by injection, includingintravenous, intraperitoneal, intramuscular, and subcutaneous injection,by transmucosal or transdermal delivery, through topical applications,nasal spray, suppository and the like or may be administered orally.Formulations may optionally be liposomal formulations, emulsions,formulations designed to administer the drug across mucosal membranes ortransdermal formulations. Suitable formulations for each of thesemethods of administration may be found, for example, in “Remington: TheScience and Practice of Pharmacy”, 20th ed., Gennaro, ed., LippincottWilliams & Wilkins, Philadelphia, Pa., U.S.A. Because seladelpar isorally available, typical formulations will be oral, and typical dosageforms will be tablets or capsules for oral administration. As mentionedin the “Seladelpar” subsection, seladelpar has been formulated incapsules for clinical trials.

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, preferably in unit dosage form suitable for single administrationof a precise dosage. In addition to an effective amount of theseladelpar, the compositions may contain suitablepharmaceutically-acceptable excipients, including adjuvants whichfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically. “Pharmaceutically acceptable excipient”refers to an excipient or mixture of excipients which does not interferewith the effectiveness of the biological activity of the activecompound(s) and which is not toxic or otherwise undesirable to thesubject to which it is administered.

For solid compositions, conventional excipients include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talc, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. Liquid pharmacologically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc., an active compound as described herein and optional pharmaceuticaladjuvants in water or an aqueous excipient, such as, for example, water,saline, aqueous dextrose, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of nontoxic auxiliaryexcipients such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, etc.

For oral administration, the composition will generally take the form ofa tablet or capsule; or, especially for pediatric use, it may be anaqueous or nonaqueous solution, suspension or syrup. Tablets andcapsules are preferred oral administration forms. Tablets and capsulesfor oral use will generally include one or more commonly used excipientssuch as lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. When liquid suspensions are used,the active agent may be combined with emulsifying and suspendingexcipients. If desired, flavoring, coloring and/or sweetening agents maybe added as well. Other optional excipients for incorporation into anoral formulation include preservatives, suspending agents, thickeningagents, and the like.

Typically, a pharmaceutical composition of seladelpar, or a kitcomprising compositions of seladelpar, is packaged in a container with alabel, or instructions, or both, indicating use of the pharmaceuticalcomposition or kit in the treatment of an intrahepatic cholestaticdisease.

A suitable amount of seladelpar or a salt thereof for oral dosing isexpected to be 5-50 mg/day, preferably 10-35 mg/day, when the amount iscalculated as seladelpar, for an adult subject with an intrahepaticcholestatic disease, depending on the disease and stage of disease andfactors such as hepatic and renal function. That is, a suitable amountof seladelpar for oral dosing for adults in diseases such as PSC and PBCwill be at or below the low end of the amounts employed in previousclinical trials but within the range of the trial described in Example2. Suitable reductions in dose toward the lower end of the outer rangeabove will be made for subjects who are children in diseases such as ASand PFIC, depending on such additional factors as age and body mass.

A person of ordinary skill in the art of the treatment of intrahepaticcholestatic disease will be able to ascertain a therapeuticallyeffective amount of the seladelpar or an seladelpar salt for aparticular disease, stage of disease, and patient to achieve atherapeutically effective amount without undue experimentation and inreliance upon personal knowledge and the disclosure of this application.

EXAMPLES Example 1

The trial subjects were adult, male or female, with a diagnosis of PBCby at least two of the following three criteria: (a) a history ofalkaline phosphatase (ALP) above the upper limit of normal (ULN) for atleast six months, (b) positive anti-mitochondrial antibody titers> 1/40on immunofluorescence or M2 positive by enzyme linked immunosorbentassay or positive PBC-specific antinuclear antibodies, and (c)documented liver biopsy result consistent with PBC, on a stable andrecommended dose of UDCA for the past twelve months, and ALP≥1.67×ULN.Exclusion criteria included AST or ALT≥3×ULN, total bilirubin(TBIL)≥2×ULN, autoimmune hepatitis or a history of chronic viralhepatitis, PSC, the current use of fibrates or simvastatin, the use ofcolchicine, methotrexate, azathioprine, or systemic steroids in theprevious two months, the use of an experimental treatment for PBC, andthe use of an experimental or unapproved immunosuppressant. The primarystudy endpoint was decrease in ALP, and the secondary endpoint was theresponder rate for subjects achieving ALP<1.67×ULN and total bilirubinwithin normal limit, and >15% decrease in ALP. Additional secondaryendpoints were changes in GGT, TBIL, and 5′-nucleotidase, which areother recognized biochemical markers of cholestasis. Subjects wererandomized to receive either placebo, 50 mg/day, or 200 mg/day ofseladelpar orally for 12 weeks. During the study, three cases ofasymptomatic increases in transaminases were observed (two in the 200 mgand one in the 50 mg groups). All three were reversible on cessation oftreatment and were not accompanied by elevation of TBIL. Since the studyhad already shown a clear efficacy signal, the study was discontinued.After the study was unblinded, changes in the primary endpoint ALP wereanalyzed using data available for the 26 subjects (10 in the placebogroup, 9 in the 50 mg/day seladelpar group, and 7 in the 200 mg/dayseladelpar group) enrolled in the study and completing at least twoweeks of treatment. According to the original statistical plan, changesin ALP were calculated using the last observation carried forward. Themean decreases from baseline in ALP for the 50 mg/day and 200 mg/daydose groups were 57% and 62%, respectively, compared with 0.37% forplacebo (p<0.0001 for both). The responder rates for the placebo, 50mg/day, and 200 mg/day groups were 10%, 67% and 100%, respectively,despite the baseline ALP levels being different at 239, 313, and 280U/L. The p-values comparing the responder rates for the 50 mg/day and200 mg/day groups with placebo were 0.020 and 0.0004 (Fisher's ExactTest), respectively. Thus, seladelpar exhibits a rapid and potentanti-cholestatic effect in subjects with PBC. The lack of a doseresponse suggested that lower doses could be effective as well. Since arecently completed preclinical study with seladelpar showed that themain route of elimination of the drug is through bile and that the drugis concentrated in bile, and since subjects with PBC have impaired bileflow, the exposure of the drug to the liver in subjects with PBC couldhave been higher than in prior clinical studies in subjects with normalliver function, explaining both the more potent anticholestatic effectand the transaminase effects. The subjects receiving seladelpar alsodemonstrated improvements in metabolic parameters, including reductionsof LDL-C of 16 and 26% for the 50 mg/day and 200 mg/day dose groups,respectively, vs. 0.8% for placebo after two weeks of dosing. It is alsonoteworthy that, despite the potent anti-cholestatic effect, no adverseevents of pruritus were reported on treatment.

Example 2

Adult subjects with an intrahepatic cholestatic disease such as PBC aretreated orally with doses of 5, 10, 25, or 50 mg/day of seladelpar.Subjects are permitted their usual other medications, including UDCA.The subjects are assessed before the study, and at intervals during thestudy, such as every 4 weeks during the study and 4 weeks after the lastdose of the seladelpar therapy, for safety and pharmacodynamicevaluations. At each visit, after a 12-hour fast, blood is drawn andurine collected; and a standard metabolic panel, complete blood count,and standard urinalysis are performed. Blood is analyzed for TC, HDL-C,TG, VLDL-C, LDL-C, and apolipoprotein B, for liver function markers suchas total and bone-specific alkaline phosphatases, for γ-glutamyltranspeptidase, and also for total and conjugated bilirubin. Thesubjects also maintain health diaries, which are reviewed at each visit.The subjects show an improvement in their disease, as manifested by, forexample, a decrease in ALP and GGT.

While this invention has been described in conjunction with specificembodiments and examples, it will be apparent to a person of ordinaryskill in the art, having regard to that skill and this disclosure, thatequivalents of the specifically disclosed materials and methods willalso be applicable to this invention; and such equivalents are intendedto be included within the following claims.

What is claimed is:
 1. A method of treating an intrahepatic cholestaticdisease by administering seladelpar or a salt thereof, where the dailydose of seladelpar or a salt thereof is 5 mg, when the dose iscalculated as seladelpar.
 2. The method of claim 1 where the seladelparor a salt thereof is seladelpar L-lysine dihydrate salt.
 3. The methodof claim 1 where the seladelpar or a salt thereof is administeredorally.
 4. The method of claim 2 where the seladelpar L-lysine dihydratesalt is administered orally.
 5. The method of claim 1 where theseladelpar or a salt thereof is administered once/day.
 6. The method ofclaim 2 where the seladelpar L-lysine dihydrate salt is administeredonce/day.
 7. The method of claim 3 where the seladelpar or a saltthereof is administered once/day.
 8. The method of claim 4 where theseladelpar L-lysine dihydrate salt is administered once/day.
 9. A methodof treating an intrahepatic cholestatic disease by administeringseladelpar or a salt thereof, where the daily dose of seladelpar or asalt thereof is 10 mg, when the dose is calculated as seladelpar. 10.The method of claim 9 where the seladelpar or a salt thereof isseladelpar L-lysine dihydrate salt.
 11. The method of claim 9 where theseladelpar or a salt thereof is administered orally.
 12. The method ofclaim 10 where the seladelpar L-lysine dihydrate salt is administeredorally.
 13. The method of claim 9 where the seladelpar or a salt thereofis administered once/day.
 14. The method of claim 10 where theseladelpar L-lysine dihydrate salt is administered once/day.
 15. Themethod of claim 11 where the seladelpar or a salt thereof isadministered once/day.
 16. The method of claim 12 where the seladelparL-lysine dihydrate salt is administered once/day.